Background: Bloodstream infections (BSI) in cancer patients remain associated with significant morbidity and mortality. The choice of an empirical antibiotic regimen is usually based on the local epidemiology of the microorganisms and their antimicrobial susceptibility profile. We present the spectrum and the antimicrobial susceptibility of the causative agents of BSI in adult cancer patients in East Sussex Healthcare Trust (ESHT), UK.Materials and Methods: This retrospective study was conducted at ESHT from January 2006 to December 2015. Demographic and laboratory data were collected from the pathology information system.Results: A total of 640 episodes of BSI occurred in 297 patients (159 male). Of the 297 patients, 239 (80%) had haematology malignancies, whereas 54 (18%) had solid organ tumours. Four patients had both. Majority of BSI (383, 60% episode) occurred in neutropenic patients. A total of 802 organisms (477 [59%] and 325 [41%] organisms from neutropenic and non-neutropenic patients, respectively) were isolated. Of 802, 406 (51%) Gram-positive and 386 (49%) Gram-negative organisms were isolated. Seven Mycobacterium species and three Candida species were isolated. Most common organisms in neutropenic patients were coagulase-negative Staphylococcus (CoNS) (22%), Klebsiella species (14%), Escherichia coli (13%), Streptococcus species (10%) and Pseudomonas species (10%). In non-neutropenic patients, CoNS (29%), E. coli (11%), Pseudomonas species (8%), Streptococcus species (7%) and Klebsiella species (5%) were isolated. Twelve glycopeptide-resistant Enterococci (26% of total 47 Enterococcus species) were isolated. Four methicillin-resistant Staphylococcus aureus (14% of total 28 S. aureus) were isolated. Furthermore, 15 extended-spectrum β-lactamase producing Gram-negative bacilli were isolated. Among Gram-negative organisms, more than 91% isolates were sensitive to piperacillin/tazobactam, ceftazidime and ciprofloxacin and higher sensitivity rates (>95%) were recorded in gentamicin, polymyxin B and meropenem.Conclusion: This study highlights an ongoing trend towards Gram-positive organisms causing BSI in cancer patients. The antimicrobial regimens used in our institution are highly effective against commonly isolated organisms. The identification and the antimicrobial susceptibility of the microorganisms causing BSI in cancer patients remain important to develop antimicrobial treatment strategies including antimicrobial guidelines as well as infection control and to prevent the spread of antimicrobial resistance.

Patients with haematology or solid organ malignancies are prone to acquire life-threatening infections not only because of the underlying disease but also due to neutropenia induced by the use of cytotoxic drugs or due to bone marrow failure.[1] Bloodstream infections (BSI) caused by the bacteria or fungi in cancer patients are directly associated with prolonged hospital stay, increased healthcare costs and significant morbidity and mortality.[2],[3] One case–control study reported that neutropenia for more than 6 days and use of central venous catheter are important risks factors for BSI in cancer patients.[4] Mortality rates of adult patients with neutropenic sepsis have been reported the range between 25% and 32%.[5] Early diagnosis and prompt administration of the antimicrobial therapy including supportive therapy are crucial steps in reducing sepsis-related morbidity and mortality.[6],[7],[8] A shift from the predominance of Gram-negative organisms such as Escherichia More Details coli, Klebsiella species, Pseudomonas species in the 1970s and 80s to the predominance of Gram-positive organisms such as Staphylococcus species, Streptococcus species, Enterococcus species in 1980s and 90s has been observed.[9],[10] Antimicrobial resistance among the organisms is a major concern worldwide. It has serious consequences in cancer patients with infections such as treatment failure, prolonged infections and fatal outcome. One study showed the emergence of fluoroquinolone resistance (commonly used oral agent as prophylaxis) in Gram-negative bacteria causing BSI in cancer patients.[11] Regular surveillance of the microbiological spectrum of BSI and the antimicrobial resistance of the causative agents allows evaluation of antimicrobial management strategies and their implementation and helps to reduce the emergence of multidrug-resistant organisms. Antimicrobial guidelines for empirical therapy based on the local prevalence of the microorganisms and their susceptibility profile play an important role in managing BSI as compared to national empirical antimicrobial therapy guidelines.[12] In this study, we intend to describe the epidemiology and the antimicrobial resistance of BSI among cancer patients in East Sussex Healthcare Trust (ESHT), England, United Kingdom.

Materials and Methods

Study location and patients

This retrospective study was conducted by two consultants (microbiology and haematology) and one senior biomedical scientist at the pathology laboratory at ESHT from January 2006 to December 2015. ESHT provides services at two district general hospitals to the half million population of the Southeast of England. Both hospitals provide services to medical and surgical subspecialities including haematology, oncology, paediatrics, gynaecology and obstetrics, orthopaedics and dermatology. All cancer patients with a positive blood culture were identified from the pathology information system and included in this study. Demographic and laboratory data were collected from the pathology information system. BSI was defined as at least one bottle from a blood culture set positive for microbe on cancer patient. Neutropenia was defined as a neutrophil count <1.0 × 109/L.

In ESHT, a clear antimicrobial guideline [13] for the management of sepsis in cancer patients with or without neutropenia has been implemented as a part of sepsis bundle. The antimicrobial guidelines for the management of sepsis in cancer patients recommend piperacillin/tazobactam as a monotherapy as the first line, and gentamicin is added in case of septic shock or if Pseudomonas infection is suspected or the blood culture is positive, or there are no signs of improvement. Vancomycin is also added as a first line therapy if there is a suspicion of central line sepsis. Alternative therapies are meropenem or ceftazidime or ciprofloxacin with or without aminoglycoside.

The primary outcome was to evaluate the spectrum of bloodstream isolates and focusing on sensitivity rates of the antibiotics used to treat cancer patients with BSI in our hospital.

Ethical consideration

This study was approved by the audit committee at ESHT (approval number 3970/2016).

Of total 640 episodes of BSI, 383 (60%) occurred in neutropenic patients (neutrophil count: <1.0 × 109/L). A total of 802 organisms (477 [59%] and 325 [41%] organisms from neutropenic and non-neutropenic, respectively) were isolated. Of 802, 406 (51%) Gram-positive (241 (59%) and 165 (41%) in neutropenic and non-neutropenic patients, respectively) and 386 (49%) Gram-negative organisms (232 [60%] and 154 [40%] in neutropenic and non-neutropenic patients, respectively) were isolated. Seven Mycobacterium species and three Candida species were also isolated. Seventeen anaerobic (Gram-positive anaerobes 9 and Gram-negative 8) were isolated during this study. Five and four Gram-positive anaerobes were isolated from neutropenic and non-neutropenic patients, respectively, while three and five Gram-negative anaerobes caused BSI in neutropenic and non-neutropenic patients respectively.

Most commonly isolated organisms in neutropenic patients were coagulase-negative Staphylococcus (CoNS) (22%), Klebsiella species (14%), Escherichia coli (13%), Streptococcus species (10%), Pseudomonas species (10%), Enterococcus species (8%) and Staphylococcus aureus (4%). In non-neutropenic patients, CoNS (29%), E. coli (11%), Pseudomonas species (8%), Streptococcus species (7%) and Klebsiella species (5%) were isolated [Figure 3]. A total of 12 glycopeptide-resistant Enterococci (GRE) (26% of total 47 Enterococcus species) were isolated which were resistant to vancomycin and teicoplanin. Four methicillin-resistant S. aureus (MRSA) (14% of total 28 S. aureus) were isolated. In this study, 15 extended-spectrum beta-lactamase (ESBL) producing Gram-negative Enterobacteriaceae caused BSI in cancer patients.

Antibiotic resistance to Methicillin was found in 14% of S. aureus isolates during this study. No antibiotic resistance to vancomycin, rifampicin was detected in S. aureus, whereas only 4% were resistant to tetracycline. Of total 28, 11% S. aureus were resistant to rifampicin and erythromycin. All Streptococcus A, B, G were sensitive to amoxicillin, penicillin, erythromycin and vancomycin. On the other hand, 26% Enterococci species were resistant to glycopeptides. The antimicrobial sensitivity pattern of Gram-positive cocci is summarised in [Table 2].

Table 2: Antibiotic sensitivity rate in most common Gram-positive organisms

Among Gram-negative organisms, low-level resistance (9%) to piperacillin/tazobactam, ceftazidime and ciprofloxacin was recorded. In this study, higher sensitivity rate (>95%) was recorded in gentamicin, polymyxin B and meropenem. Majority of Gram-negative organisms are sensitive to the first-line empirical therapy used in our hospital [Table 3]. Among all Gram-positive cocci, 3% remained resistant to vancomycin [Table 4].

Bacteraemia in cancer patients could be life-threatening unless it is managed promptly, in timely fashion with appropriate antimicrobial therapy and source control. Appropriate empirical antimicrobial therapy is based on the spectrum of local flora and their antibiotic susceptibility pattern. This strategy has become more important in present era when antimicrobial resistance is rising, and the emergence of multidrug-resistant organisms may lead to devastating complications of infection in cancer patients. Similar to other infections, the occurrence of BSI increases with age and incidence of BSI is influenced by several other physiological factors such as cancer, lengthy hospital stay and gastrointestinal pathology.[14] In this study, 62.28% of patients with BSI were more than 65 years old which is consistent with the previous study.[14] Only a small number of patients (8%) with BSI were <40 years old.

This study reports an ongoing trend towards Gram-positive organisms (51%) such as CoNS, Streptococcus species, S. aureus, Enterococcus species and Gram-positive bacilli causing BSI in both neutropenic and non-neutropenic patients. The incidence of Gram-negative bacteria in cancer patients such as E. coli, Klebsiella species, Pseudomonas was 48% in our institution. The predominance of Gram-positive organisms in this study is consistent with the previous study.[4] On the contrary, patients with neutropenia are at increased risk of Gram-negative BSI due to severe and persistent impaired host defences.[15] The spectrum of BSI in cancer patients has changed markedly in the past three decades. Several studies have also reported a shift from BSI due to Gram-negative organisms towards Gram-positive organisms in cancer patients.[11],[16] One Spanish study reported a similar trend in 288 episodes of neutropenia on 320 patients where 200 (63%) and 120 (36%) were Gram-positive and Gram-negative organisms, respectively.[16] On the contrary, other studies reported the prevalence of Gram-negative organisms in BSI in cancer patients.[3],[11] The possible reasons for Gram-positive organism predominance could be the frequent use of intravascular lines for chemotherapy, use of antibiotic prophylaxis such ciprofloxacin and antifungal prophylaxis and underlying disease. Candida infections are an important cause of BSI in cancer patients with intravascular devices. This study also disclosed an important point that fungal infections were uncommon in both neutropenic and non-neutropenic groups of cancer patients. Patients with poor performing immune status and influence of underlying disease are at increased risk of BSI.[4],[15] Our study confirms previous studies and Majority of BSI episodes occurred in the neutropenic group.

Gram-negative bacteria are associated with multidrug resistance, especially carbapenem resistance and it has been the cause of public health concern in recent years. One study reported the increase of antimicrobial resistant Gram-negative organism causing BSI in cancer patients. Approximately 29% and 9% of total 43 Gram-negative organisms were resistant to third-generation cephalosporins and carbapenems, respectively.[17] This study reported <10% antimicrobial resistance in Gram-negative organisms to gentamicin, piperacillin/tazobactam, ceftazidime, polymyxin B and meropenem. Ciprofloxacin resistance in all Gram-negative organism was also <10% in this study, whereas other studies reported the emergence of quinolone resistance in cancer patients.[11],[18] No carbapenemase-producing organism was isolated in this study. Despite being the use of quinolones as antibiotic prophylaxis in neutropenic cancer patients in our centre, the resistance rate was low. No multidrug-resistant Acinetobacter species were isolated which pose real therapeutic challenge to the clinicians. Piperacillin/tazobactam, meropenem, ciprofloxacin, ceftazidime with or without aminoglycoside are recommended by our Trust to treat cancer patients with febrile neutropenia. Vancomycin is also added to above mentioned regimens in case of line-related sepsis. These antibiotics were tested against all Gram-negative organisms causing BSI in cancer patients regardless of their neutrophil count. The antibiotic susceptibility data suggested that these regimens are an appropriate choices in empirical use for febrile neutropenia in our hospitals [Table 3] and [Table 4]. There are growing concerns about BSI due to MRSA and ESBL producing Enterobacteriaceae as they are resistant to commonly used antibiotics. This study shows low incidence of MRSA bacteraemia (4 cases) which accounted 14% of total S. aureus (28) BSI. The prevalence of MRSA is low as compared to other studies.[7],[19] The low incidence of MRSA bacteraemia may be due to implementation of antimicrobial guidelines, good infection prevention and control practice, prompt MRSA screening of the risk patients, timely delivery of MRSA results, isolation of patients with MRSA colonisation/infection without any delay initiation of MRSA decolonisation and antibiotic therapy in case of infection. Twelve GRE caused BSI in cancer patients which made up of 26% of total Enterococci. In one study, Cattaneo et al. reported 23.1% GRE caused BSI.[11] The prevalence of GRE in study was higher than the previous study.[11] High prevalence of GRE indicated the higher use of glycopeptide antimicrobials in cancer patients. Cancer patients usually have intravascular devices for chemotherapy or other drugs which could become colonised and infected with microorganisms. Glycopeptide antimicrobials are frequently used to treat line-related sepsis. Nevertheless, 97% of Gram-positive organisms in this study were sensitive to the glycopeptide antibiotic. ESBL-producing Enterobacteriaceae are usually multidrug-resistant organisms, resistant to penicillin, as well as cephalosporins and they pose a real therapeutic challenge to the clinicians including microbiologists. In this study, 15 (2.34% of total 640 positive blood cultures) ESBL-producing Gram-negative organisms were isolated. Of 15 ESBL-producing Enterobacteriaceae, 7, 6, 2, were Klebsiella species, E. coli and Enterobacter species, respectively. The prevalence of ESBL producing bacteraemia is lower than previously reported study.[20] Kurtaran et al. from Turkey reported a high prevalence of ESBL among E. coli and Klebsiella BSI in cancer patients over 3-year period (69.6%, 40% and 79.2% in years 2005, 2006 and 2007, respectively). In our study, all ESBL-producing organisms were sensitive to meropenem and polymyxin B while four were resistant to gentamicin.

Conclusion

The present study describes the spectrum of microorganisms causing BSI in a high-risk group of patients. Gram-positive organisms were predominant in this study. Antibiotic susceptibility pattern on isolated organisms supported the current antimicrobial regimens for BSI in cancer patients with or without neutropenia. Antimicrobial resistance was low in this study. When infection due to multidrug-resistant organism such as ESBL-producing Enterobacteriaceae or Gram-positive organism, is suspected, a carbapenem with or without aminoglycoside or a glycopeptide agent should be considered to treat BSI in case MRSA infection. An early diagnosis and timely administration of appropriate antibiotics are imperative in managing BSI. The continuous surveillance of BSI in cancer patients helps to prevent unnecessary use of broad-spectrum antibiotics and reduce the selection of resistant organism.